Disturbances in hormone secretion have been frequently described in depressed patients. To date there have been few attempts to develop models to explain these pathophysiological disturbances. Hormone secretion is both pulsatile and periodic with each neuroendocrine axis being tonically modulated through trophic activation an negative feedback inhibition. The activity within any axis is therefore rhythmic and specific patterns of activation have been described in different axes. Such patterns are reproducible and imply synchronized interactions between the different components of a neuroendocrine axis as well as between axes. This complex process is ultimately regulated by the interaction between a hormone and its specific target cell receptor. While it is the target cell responses which are ultimately measured, it is clear they tell little about subtale changes in synchronization and regulation at different levels within a neuroendocrine axis. This proposal focuses upon the regulation and synchronization of biological rhythms in depressed patients. It is anticipated that during a depressive illness there is a disruption in the normal phasic relationships of these rhythms which could result in the previously described disturbances in hormone secretion. With treatment and clinical recovery it is expected that the relationship between these rhythms will change and approach that found in healthy control subjects. It is proposed to study the hypothalamic-pituitary-adrenal axis in some detail and determine the phase relationships both within the axis as well as with other well established rhythms like the rest-activity cycle and core body temperature. This will be accomplished by monitoring activity and sleep as well as measuring core body temperature and plasma concentrations of cortisol, ACTH, Beta-LPH and Beta-endorphin over a 24-hour period. These data will allow direct comparison of the phase relationships between these rhythms as well as within the axis. Internal synchronization within the axis can be explored further by establishing the sensitivity of the axis to CRF and ACTH at discrete times during the day. Since the hormone disturbances described in depression reverse with clinical recovery, these studies should provide important new information about the nature of the pathophysiological disturbances which have been previously described in the hypothalamic-pituitary-adrenal axis.